Red rice extracts promote Nrf2-dependent neuroprotection through coordinated redox and metabolic remodeling under acute and chronic oxidative stress

Oxidative stress is a major contributor to neuronal injury and neurodegeneration. However, how Nrf2-dependent redox regulation coordinates metabolic remodeling during acute and chronic oxidative stress remains unclear. Although red rice contains antioxidant bioactive compounds, their effects on redox regulation and metabolic adaptation have not been systematically investigated. In this study, complementary HT22 models of acute glutamate-induced oxidative stress and chronic differentiation-associated degeneration were used to investigate neuronal responses under distinct stress conditions. Red rice extracts were evaluated for their effects on neuronal viability, reactive oxygen species (ROS), glutathione homeostasis, and Nrf2 signaling. The role of Nrf2 activity was examined using pharmacological inhibition, nuclear translocation, and downstream antioxidant responses. Integrated amino acid metabolomics and lipidomics revealed metabolic changes associated with oxidative stress and treatment. Both models exhibited increased ROS, glutathione depletion, impaired Nrf2 signaling, and reduced neuronal viability. Red rice extracts restored redox balance, promoted Nrf2 nuclear translocation, increased Prx1 expression, and improved neuronal survival. Nrf2 inhibition attenuated these protective effects, supporting a central role for Nrf2 signaling. Metabolomic and lipidomic analyses further showed recovery of glutathione-related amino acid metabolism together with phospholipid and sphingolipid homeostasis. These findings suggest Nrf2-dependent redox regulation as a central mechanism linking oxidative stress to metabolic programming. By restoring redox homeostasis and coordinating amino acid and lipid metabolism, red rice extracts promoted neuronal adaptation under acute and chronic oxidative stress. This study provides new insight into redox-metabolic remodeling and supports the potential of red rice as a source of neuroprotective bioactive compounds.